Cell Death
( 1 ) Cancer cells die after hours, days or weeks of radiation, and continue dying for weeks after treatment. Cell deaths include apoptosis, mitotic catastrophe, necrosis, senescence and autophagy. On this page we will focus on cell death by apoptosis. ( 2 ) Apoptosis is a process found in all cells to protect an organism by triggering the death of harmful cells. The features of apoptosis are : * Blebbing happens in late apoptosis and consists of a bulge in the membrane of cells, which eventually detaches from it, breaking up the by taking parts of it forming apoptotic bodies. * Loss of cell volume * Nuclear condensation * DNA fragmentation * Formation of apoptotic body (3) This diagram illustrates the steps of apoptosis : (4) Apoptosis can be divided into an intrinsic and an extrinsic pathway : * Intrinsic pathway : The intrinsic pathway is mainly activated by internal stimuli following damage to the cell. This pathway is regulated by B-cell lymphoma 2. B-cell lymphoma proteins can be divided into two categories : pro-apoptotic proteins like Bax and Bak and anti-apoptotic proteins. In the intrinsic pathway, Bax and Bak cause the formation of pores in the membrane of mitochondria, leading to MOMP ( mitochondrial outer membrane permeabilisation ). Anti-apoptotic proteins and additional pro-apoptotic proteins can bind to Bax and Bak and either stimulate or inhibit these proteins. Following MOMP, mitochondria release effector proteins like cytochrome c that leads to activation of effector caspases like caspase-3 and ultimately cell death. A caspase is an enzyme that orchestrates programmed cell death, initially synthesised as an inactive pro-caspase before being converted into a caspase at the start of apoptosis. * The extrinsic pathway is activated when ‘death’ ligands such as TNF attach to transmembrane receptors such as TNFR1 on the target cell. The transmembrane receptor then associates with an adaptor molecule and forms DISC ( death-inducing signaling complex ). The adaptor molecule and DISC enables caspases to bind to the complex and stimulate pro-apoptotic B-cell lymphoma-2 proteins that lead to the release of cytochrome which stimulates effector caspaces like caspase Both the intrinsic and extrinsic are linked by caspase-3, one of the main effector caspase. Caspases activate each other by cleavage of signalling components that cause morphological changes in the target cell. (5) This figure illustrates the extrinsic and intrinsic pathway of apoptosis : (6) Cancer cells can become resistant to apoptosis and bypass checkpoints due to mutations of genes involved in cell control such as p53 or BRCA 1 and BRCA 2. Inhibitors of apoptosis are a group of proteins that are crucial in programmed cell death. However, uninhibited, IAP’s can also prevent cell death which leads to cell survival and the development of tumors. Pro-apoptotic factors that encourage apoptosis such as B cell lymphoma 2 proteins are inhibited in cancer cells and inhibitors of apoptosis are promoted. Study around radiotherapy and chemotherapy show that they promote stress-triggered apoptosis by damaging DNA. It is important to understand how apoptosis affects cancer cells and leads to cell death in order to prevent chemo and radio resistance and develop potential future treatments that target anti-apoptotic and pro-apoptotic proteins. This new treatment plan could prevent damage to healthy cells unlike current cancer treatments as we would be targeting inhibitors of apoptosis, only expressed excessively in cancer cells. Potential treatments plans : * Mono-therapy with IAP-antagonists * Combinatorial treatments with chemotherapeutic agent (1) Baskar R, Lee KA, Yeo R, Yeoh KW. Cancer and radiation therapy: current advances and future directions. International journal of medical sciences.2012;9(3):193. (2) Bortner CD, Cidlowski JA. Apoptotic volume decrease and the incredible shrinking cell.2002. (3) Image credit to abbexa : https://www.abbexa.com March 2019 (4)Kerr DJ, Haller DG, van de Velde CJ, Baumann M, editors. Oxford textbook of oncology. Oxford University Press; 2016 Jan 28. (5) Rampal G, Khanna N, Thind TS, Arora S, Vig AP. Role of isothiocyanates as anticancer agents and their contributing molecular and cellular mechanisms. Med. Chem. Drug Discovery. 2012;3:79-93. (6) Rathore R, McCallum JE, Varghese E, Florea AM, Büsselberg D. Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs). Apoptosis. 2017 Jul 1;22(7):898-919.